Frontiers in Immunology (Oct 2020)
The Novel Omega-6 Fatty Acid Docosapentaenoic Acid Positively Modulates Brain Innate Immune Response for Resolving Neuroinflammation at Early and Late Stages of Humanized APOE-Based Alzheimer's Disease Models
- Qiu-Lan Ma,
- Qiu-Lan Ma,
- Cansheng Zhu,
- Cansheng Zhu,
- Cansheng Zhu,
- Marco Morselli,
- Marco Morselli,
- Marco Morselli,
- Trent Su,
- Trent Su,
- Matteo Pelligrini,
- Matteo Pelligrini,
- Matteo Pelligrini,
- Matteo Pelligrini,
- Zhengqi Lu,
- Mychica Jones,
- Mychica Jones,
- Paul Denver,
- Paul Denver,
- Daniel Castro,
- Daniel Castro,
- Xuelin Gu,
- Xuelin Gu,
- Frances Relampagos,
- Frances Relampagos,
- Kaitlin Caoili,
- Kaitlin Caoili,
- Bruce Teter,
- Bruce Teter,
- Sally A. Frautschy,
- Sally A. Frautschy,
- Sally A. Frautschy,
- Gregory M. Cole,
- Gregory M. Cole,
- Gregory M. Cole
Affiliations
- Qiu-Lan Ma
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Qiu-Lan Ma
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Cansheng Zhu
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Cansheng Zhu
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Cansheng Zhu
- Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Marco Morselli
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, United States
- Marco Morselli
- Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA, United States
- Marco Morselli
- Institute for Quantitative and Computational Biology, University of California, Los Angeles, Los Angeles, CA, United States
- Trent Su
- Institute for Quantitative and Computational Biology, University of California, Los Angeles, Los Angeles, CA, United States
- Trent Su
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, United States
- Matteo Pelligrini
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, United States
- Matteo Pelligrini
- Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA, United States
- Matteo Pelligrini
- Institute for Quantitative and Computational Biology, University of California, Los Angeles, Los Angeles, CA, United States
- Matteo Pelligrini
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, United States
- Zhengqi Lu
- Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Mychica Jones
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Mychica Jones
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Paul Denver
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Paul Denver
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Daniel Castro
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Daniel Castro
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Xuelin Gu
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Xuelin Gu
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Frances Relampagos
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Frances Relampagos
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Kaitlin Caoili
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Kaitlin Caoili
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Bruce Teter
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Bruce Teter
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Sally A. Frautschy
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Sally A. Frautschy
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Sally A. Frautschy
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Gregory M. Cole
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- Gregory M. Cole
- Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Los Angeles, CA, United States
- Gregory M. Cole
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- DOI
- https://doi.org/10.3389/fimmu.2020.558036
- Journal volume & issue
-
Vol. 11
Abstract
Neuroinflammation plays a crucial role in the development and progression of Alzheimer's disease (AD), in which activated microglia are found to be associated with neurodegeneration. However, there is limited evidence showing how neuroinflammation and activated microglia are directly linked to neurodegeneration in vivo. Besides, there are currently no effective anti-inflammatory drugs for AD. In this study, we report on an effective anti-inflammatory lipid, linoleic acid (LA) metabolite docosapentaenoic acid (DPAn-6) treatment of aged humanized EFAD mice with advanced AD pathology. We also report the associations of neuroinflammatory and/or activated microglial markers with neurodegeneration in vivo. First, we found that dietary LA reduced proinflammatory cytokines of IL1-β, IL-6, as well as mRNA expression of COX2 toward resolving neuroinflammation with an increase of IL-10 in adult AD models E3FAD and E4FAD mice. Brain fatty acid assays showed a five to six-fold increase in DPAn-6 by dietary LA, especially more in E4FAD mice, when compared to standard diet. Thus, we tested DPAn-6 in aged E4FAD mice. After DPAn-6 was administered to the E4FAD mice by oral gavage for three weeks, we found that DPAn-6 reduced microgliosis and mRNA expressions of inflammatory, microglial, and caspase markers. Further, DPAn-6 increased mRNA expressions of ADCYAP1, VGF, and neuronal pentraxin 2 in parallel, all of which were inversely correlated with inflammatory and microglial markers. Finally, both LA and DPAn-6 directly reduced mRNA expression of COX2 in amyloid-beta42 oligomer-challenged BV2 microglial cells. Together, these data indicated that DPAn-6 modulated neuroinflammatory responses toward resolution and improvement of neurodegeneration in the late stages of AD models.
Keywords
